Caregiver Burden with Duchenne and Becker Muscular Dystrophy in Japan: A Clinical Observation Study.

Objective Skeletal muscle weakness and cardiomyopathy can be seen in carriers of dystrophinopathy. Therefore, the health management of caregivers of Duchenne/Becker muscular dystrophy (DMD/BMD) patients who are themselves carriers is an important issue. However, few studies have focused on caregivers who have dystrophin mutations. Methods In this cross-sectional study conducted at five hospitals, the daily living, situation medical treatment status, genetic testing, physical assessment, care burden, and quality of life of caregivers of DMD/BMD patients were surveyed. Results The subjects were 36 main caregivers (mean age 55.7±8.4 years old), of whom 52.8% were diagnosed as carriers, 8.3% were noncarriers, and 38.9% were not confirmed. In addition, half of the caregivers were not examined regularly at medical institutions. Of all caregivers, 54.3% had muscle or cardiac symptoms, and 75% had elevated serum creatine kinase levels. The mean Zarit Caregiver Burden Interview (ZBI) total score of current caregivers was 20.9±13.1. The frequency of a ZBI total score ≥25 was significantly higher in caregivers diagnosed as carriers than in caregivers unexamined as carriers (p=0.04). The health-related quality of life score (Short Form 36; SF-36) in caregivers was slightly lower than the Japanese standard scores in the sections of physical functioning, role limitations-physical, bodily pain, and social functioning. Conclusion Some caregivers of DMD/BMD patients can themselves have muscular or cardiac symptoms and a heavy care burden. It is therefore necessary for carrier caregivers, especially women, to undergo regular health checkups and receive appropriate health management.

A web-based questionnaire survey on the influence of coronavirus disease-19 on the care of patients with muscular dystrophy.

To clarify the influence of coronavirus disease-19 (COVID-19) on the care of muscular dystrophy patients, we performed a questionnaire survey that was posted on the internet on May 11, 2020. By the end of July 2020, 542 responses had been collected. Approximately 30% of patients postponed regular consultations, and one-quarter of patients who received consultation more than once a month used telephone consultations. Two of 84 patients with Duchenne muscular dystrophy had reduced their steroid doses. A shortage of ventilator accessories and infection protection equipment occurred following the onset of COVID-19, and this shortage had a serious impact on medical care and infection prevention measures. Reductions in rehabilitation and other services, and avoidance of outings, led to a decrease in exercise and an increase in caregiver burden. Inpatients were restricted from going out and visiting family members. More than 20% of patients reported physical or mental complaints; however, few required treatment. COVID-19 has seriously affected the activities and quality of life of patients with muscular dystrophy. We will continue this survey and analyze the longitudinal changes.

Renal function in amyotrophic lateral sclerosis patients on long-term treatment with edaravone.

ABSTRACT: Edaravone, a free radical-scavenger, was approved in Japan for the treatment of amyotrophic lateral sclerosis (ALS). However, the effect of the drug on renal function in ALS patients remains unclear. This study aimed to investigate renal function in ALS patients on long-term treatment with edaravone by measuring the serum estimated glomerular filtration rate based on cystatin C (eGFR-CysC).In a retrospective study, the data of ALS patients who were treated with over 10 cycles of intravenous edaravone treatment and were evaluated by eGFR-CysC before and after 10 cycles of treatment between July 2015 and June 2018 were analyzed. Then, the results were compared with those of a control ALS group that had never been treated with edaravone.There were 11 patients with ALS who received over 10 cycles of intravenous edaravone treatment. The mean interval between the first and final eGFR-CysC measurements was 18.7 ±â€Š7.9 months. Three patients (27.3%) had >20 mL/min/1.73 m2 decrease in serum eGFR-CysC. However, no patients discontinued edaravone treatment because of renal dysfunction. The average variation rate of eGFR-CysC was not different between the long-term edaravone group (0.29 ±â€Š1.07) and the control group (-0.34 ±â€Š0.40).This retrospective, single-center analysis showed no clinical exacerbation of renal function in ALS patients who received long-term treatment with edaravone.

A case report of intracholecystic papillary neoplasm of the gallbladder resembling a submucosal tumor.

BACKGROUND: Intracholecystic papillary neoplasm (ICPN) is defined as papillary tumors detected macroscopically in the gallbladder. We report a case of ICPN which exhibited the atypical form like a submucosal tumor. CASE PRESENTATION: A 70-year-old man was admitted to our hospital because of hepatic disorder. Computed tomography and magnetic resonance imaging showed irregular thickening of the wall within the gallbladder fundus. Because the lesion might have been malignant, we performed laparoscopic cholecystectomy and liver bed resection. Macroscopic findings showed the mucosal surface of the tumor was smooth, and its form was similar to that of a submucosal tumor. Histopathological examination revealed papillary tumors within the mass with low-grade dysplasia; therefore, we diagnosed ICPN. CONCLUSION: In the present case, ICPN was resembling a submucosal tumor macroscopically because the tumors arose into the Rokitansky-Aschoff sinus and the adenomyomatous hyperplasia was merged with the ICPN. It is necessary to consider the possibility of tumor lesions within adenomyomatous hyperplasia.

Long-term effects of edaravone on survival of patients with amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Oxidative stress has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Edaravone, a free radical scavenger, was approved as a therapeutic drug for ALS in 2015 in Japan. A phase 3 clinical trial demonstrated a smaller decline in ALS functional scale scores compared with placebo. However, the long-term effects of edaravone on ALS patients remain unclear. This study aimed to retrospectively investigate the long-term effects of edaravone on the survival of ALS patients. METHODS: We retrospectively analyzed 27 consecutive patients with ALS who were treated with edaravone and 30 consecutive ALS patients who were not treated with edaravone between 2010 and 2016. RESULTS: The differences of ALSFRS-R scores from baseline to 6 months was significantly reduced in the edaravone group, compared to the control group. The changes in serum creatinine, as a possible marker of ALS severity, from baseline to 6 and 12 months were significantly improved in the edaravone group, compared to the control group. The survival rate was significantly improved in the edaravone group compared with control patients. CONCLUSION: Our retrospective single-center analysis suggests slower progression and better prognosis of ALS patients with edaravone treatment. Further investigation, including prospective multicenter analysis, is warranted to confirm the usefulness of edaravone for a better prognosis of ALS.

Female dystrophinopathy: Review of current literature.

Skeletal muscle or cardiac symptoms are known to appear in a certain proportion of female patients carrying the dystrophin gene mutation. There is limited high-quality evidence to guide the treatment of female carriers of Duchenne muscular dystrophy/Becker muscular dystrophy (DMD/BMD). The available evidence is mainly based on expert opinions and clinical experience. To improve this situation, we reviewed 1002 reports published from 1967 to 2017 to assess the following themes: epidemiology, clinical symptoms, cardiomyopathy, burdens on parents or caregivers, pregnancy or delivery, and prognosis. We aimed to provide guidance for the provision of support, care, and education for patients, caregivers, and health care professionals. There were 271 reports before 1987, and 731 reports after 1987 when dystrophin was first recognized. In this review, we mainly selected 37 papers that were reported after 1987. In seven large research papers, the incidence of skeletal muscle damage among female carriers, including asymptomatic carriers, was reported as 2.5%-19%, and the incidence of dilated cardiomyopathy was 7.3%-16.7% for DMD and 0%-13.3% for BMD. We integrated and summarized the genetically definite manifesting carriers with skeletal muscle symptoms from 10 case series. In combined data, among 93 manifesting carriers, 16 (17.2%) presented with cardiac abnormalities. The frequency of manifesting carriers complicated by cardiomyopathy increased with age. Reports on cardiac magnetic resonance in female carriers and the burden on caregivers are increasing, whereas literatures concerning pregnancy, delivery, and prognosis in female carriers are limited. This represents a future direction for research.

Medical Attitudes Survey for Female Dystrophinopathy Carriers in Japan.

Objective This study attempted to clarify the current status of female dystrophinopathy carriers, including the numbers of patients, the status of genetic screening, the status of counseling, physicians' understanding, and barriers to registration. Methods We sent out questionnaires to 402 physicians registered in the Remudy dystrophinopathy registry. The total number of responses received was 130 (response rate: 32%). Result In total, 1,212 cases of Duchenne muscular dystrophy, 365 cases of Becker muscular dystrophy, and 132 cases of female dystrophinopathy with a confirmed genetic mutation were encountered, and genetic testing was performed in the mother in 137, 23, and 12 cases, respectively. With respect to the risk of the onset of health problems, 25% of physicians always explained, 29% usually explained, 29% sometimes explained, and 13% never explained the risk to the mothers and female siblings of dystrophinopathy patients. The most common reason for not explaining the risk was a lack of knowledge/information. Thirty-five percent were familiar with the guidelines for testing the heart function of carriers. Conclusion Fewer mothers of dystrophinopathy patients have undergone genetic testing in Japan than in other countries. A significant portion of doctors did not explain the risks of health problems due to a lack of knowledge. We hope this survey will lead to an increased discussion of female dystrophinopathy patients.

Detection and management of cardiomyopathy in female dystrophinopathy carriers.

Regular health checkups for mothers of patients with Duchenne muscular dystrophy have been performed at National Hospital Organization Tokushima Hospital since 1994. Among 43 mothers participated in this study, 28 dystrophinopathy carriers were identified. Skeletal and cardiac muscle functions of these subjects were examined. High serum creatine kinase was found in 23 subjects (82.1%). Obvious muscle weakness was present in 5 (17.8%) and had progressed from 1994 to 2015. Cardiomyopathy was observed in 15 subjects (60.0%), including dilated cardiomyopathy-like damage that was more common in the left ventricular (LV) posterior wall. Late gadolinium enhancement on cardiac MRI was found in 5 of 6 subjects, suggesting fibrotic cardiac muscle. In speckle tracking echocardiography performed seven years later, global longitudinal strain was decreased in these subjects, indicating LV myocardial contractile abnormality. These results suggest that female dystrophinopathy carriers should receive regular checkups for detection and treatment of cardiomyopathy, even if they have no cardiac symptoms.

[A case of myasthenia-like symptoms induced by cibenzoline overdosage].

The present patient was an 87-year-old man who had been taking cibenzoline for tachyarrhythmia. Five years after initiation of administration, he was referred to our hospital for ptosis that worsened from midday, as well as weakness of the facial and limb muscles. He tested negative for anti-acetylcholine receptor antibody but positive in the edrophonium test, suggesting that he had myasthenia gravis. He was admitted to our hospital 3 years later due to worsening symptoms of ptosis and muscle weakness. He had hypoglycemia, cardiac conduction defect, and renal dysfunction. In addition, blood concentration of cibenzoline was markedly high (1,850 ng/ml). We terminated the administration of cibenzoline, after which the patient's neurologic symptoms improved. Our findings suggest that cibenzoline toxicity must be considered in differentiating myasthenia gravis when a patient also presents with renal dysfunction.

The effects of the Kumamoto earthquake on the clinical symptoms of patients with Parkinson's disease.

Our hospital is the designated treatment base for intractable neurological diseases in the Kumamoto Prefecture. It is located in the center of the prefecture where the major 7.3-magnitude Kumamoto earthquake was recorded in 2016. In order to examine whether this earthquake affected the clinical symptoms of patients with Parkinson's disease in this hospital, we investigated outpatients examined up to 4 weeks after the earthquake. The subjects were 26 consecutive patients without any changes in anti-Parkinson's disease treatment or their attending physician during the examination period. All of the items in Part III of the Unified Parkinson's Disease Rating Scale (UPDRS), which is a clinician-scored scale for monitoring and evaluating motor function, were confirmed with the subjects before and after the earthquakes. After the earthquakes, worsened symptoms were found in 7 patients and 7 patients felt better. On the UPDRS, worsened symptoms were most commonly found among the items examining "muscle rigidity" and "slowness of movement and decreased movement" among the 7 patients with exacerbated symptoms. After the earthquake, clinical symptoms worsened significantly in women (P = 0.0188), patients with mild symptoms (P = 0.0111), and those who suffered a high degree of personal loss, such as those whose homes were damaged, who were forced to take refuge, or who had to sleep in their car (P = 0.0184). The mental and emotional burden due to the earthquake might be particularly high in the group of patients with worsened symptoms, suggestive of a relationship between stress and the exacerbation of parkinsonian symptoms.

[Low-Dose and Interval Administration of Imatinib in a Patient with Liver Metastasis of the Gastrointestinal Stromal Tumor of the Stomach - A Case Report].

A 69-year-old woman underwent proximal gastrectomy with distal pancreatectomy and splenectomy for a gastrointestinal stromal tumor of the stomach.Adjuvant imatinib was administered for a year.Two years after resection of the tumor, liver metastasis in S8 was detected.Therefore, imatinib was re-administered at 300mg/day.After a year of re-administration, the patient suffered muscle cramps in the hands, and therefore imatinib was administered with intervals, such as 4 weeks administration and 4 weeks rest.Re -administration of imatinib was effective and her liver metastasis decreased in size.It was not detected with CT after 1 year and 4 months and remained in complete response(CR)for 3 years and 8 months.After she suffered a brain infarction, imatinib administration was stopped for 4 months.Consequently, the liver metastasis was detectable in S8 again.This clinical course suggested that low-dose and interval administration of imatinib is effective in the treat- ment of GIST.

Acute Multiple Cerebral Infarction in a Patient with an Accessory Mitral Valve.

A 96-year-old woman developed hemiparesis 2 weeks after orthopedic surgery. Magnetic resonance imaging revealed multiple cerebral infarctions in the bilateral hemisphere. Transthoracic echocardiography revealed a mobile structure attached to the anterior mitral leaflet that protruded toward the left ventricular outflow tract. The structure was identified as an accessory mitral valve. Doppler echocardiography showed that there was no significant left ventricular outflow obstruction. This is a rare case of a silent accessory mitral valve that was detected after multiple cerebral infarctions.

Utility of skinfold thickness measurement in non-ambulatory patients with Duchenne muscular dystrophy.

Nutritional disorders in Duchenne muscular dystrophy (DMD) worsen the medical condition. In particular, obesity is a serious problem that increases the risk of cardiomyopathy and affects nursing care. However, it is often difficult to evaluate body fatness in the advanced stages of DMD. Skinfold thickness measurement is a classical method to evaluate body fatness and is easily performed, even for bed-bound patients at home. We aimed to investigate the utility of skinfold thickness measurement in non-ambulatory DMD patients. Twenty-two patients with non-ambulatory, steroid-naive DMD ranging in age of 12-47 years were evaluated by body mass index (BMI), blood tests, measurement of triceps skinfold thickness (TSF), and abdominal computed tomography (CT) measurement of the areas of both subcutaneous and visceral fat. TSF showed good correlation with BMI (r = 0.80; p < 0.001), serum triglycerides (r = 0.67; p < 0.01), area of subcutaneous fat (r = 0.85; p < 0.0001), and area of visceral fat (r = 0.76; p < 0.0001). These results indicate the skinfold thickness measurement may be applicable as a screening tool in clinical practice where CT and magnetic resonance imaging assessment is often difficult in patients with advanced DMD.

Ten-Year Survival of a Patient Treated with Stereotactic Gamma Knife Radiosurgery for Brain Metastases from Colon Cancer with Ovarian and Lymph Node Metastases: A Case Report.

Brain metastasis from colorectal cancer is infrequent and carries a poor prognosis. Herein, we present a patient alive 10 years after the identification of a first brain metastasis from sigmoid colon cancer. A 39-year-old woman underwent sigmoidectomy for sigmoid colon cancer during an emergency operation for pelvic peritonitis. The pathological finding was moderately differentiated adenocarcinoma. Eleven months after the sigmoidectomy, a metastatic lesion was identified in the left ovary. Despite local radiotherapy followed by chemotherapy, the left ovarian lesion grew, so resection of the uterus and bilateral ovaries was performed. Adjuvant chemotherapy with tegafur-uracil (UFT)/calcium folinate (leucovorin, LV) was initiated. Seven months after resection of the ovarian lesion, brain metastases appeared in the bilateral frontal lobes and were treated with stereotactic Gamma Knife radiosurgery. Cervical and mediastinal lymph node metastases were also diagnosed, and irradiation of these lesions was performed. After radiotherapy, 10 courses of oxaliplatin and infused fluorouracil plus leucovorin (FOLFOX) were administered. During FOLFOX administration, recurrent left frontal lobe brain metastasis was diagnosed and treated with stereotactic Gamma Knife radiosurgery. In this case, the brain metastases were well treated with stereotactic Gamma Knife radiosurgery, and the systemic disease arising from sigmoid colon cancer has been kept under control with chemotherapies, surgical resection, and radiotherapy.

Survey on genetic counseling and health management for symptomatic and asymptomatic female dystrophinopathy carriers in Japan today.

To clarify the current status of genetic counseling and health monitoring for symptomatic and asymptomatic female carriers of dystrophinopathy (Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD)), we sent out questionnaires to 104 member institutions of The Japan's National Liaison Council for Clinical Sections of Medical Genetics, and responses were received from 51 institutions. Between April 2013 and March 2014, 57 carriers at 21 institutions received genetic counseling, and 37 carriers at 15 institutions underwent genetic screening for DMD/BMD mutations. At the 23 institutions that gave genetic counseling, 20 (87%) informed carriers of possible health problems, 14 (61%) informed carriers of cardiomyopathy and heart failure, and 14 (61%) advised carriers about regular medical checkups. Evidence based on accurate and up-to-date epidemiological studies of female carriers is needed and should be widely shared with the families, medical providers, and society.

Life-threatening Arrhythmias in a Becker Muscular Dystrophy Family due to the Duplication of Exons 3-4 of the Dystrophin Gene.

We herein present a report of three patients with Becker muscular dystrophy in the same family who developed complete atrioventricular block or ventricular tachycardia with severe cardiomyopathy. Our cases became unable to walk in their teens, and were introduced to mechanical ventilation due to respiratory muscle weakness in their twenties and thirties. In all three cases, a medical device such as a permanent cardiac pacemaker or an implantable cardiac defibrillator was considered to be necessary. The duplication of exons 3-4 in the dystrophin gene was detected in two of the patients. In patients with Becker muscular dystrophy, complete atrioventricular block or ventricular tachycardia within a family has rarely been reported. Thus attention should be paid to the possibility of severe arrhythmias in the severe phenotype of Becker muscular dystrophy.

[Two cases of Duchenne muscular dystrophy over 40 years after onset].

We report two 45 year old men with Duchenne muscular dystrophy. Case 1 showed a deleted exon 50 of the dystrophin gene by MLPA analysis, and Case 2 showed deleted exons 46-52. Both patients presented with severe weakness of the skeletal muscles and respiratory dysfunction, while cardiac involvement was mild and cognitive function was almost normal. The patients are able to shop at a mall, participate in activities, and attend hobbies, although they are bedridden with artificial respiration through tracheotomy. With the progress of the respiratory care and cardiac protective therapy, the prognosis of Duchenne muscular dystrophy has improved remarkably. At present, it is possible to survive over 40 years with maintenance of quality of life, if cardiac damage is not severe.